Cholinergic neurons of the medial forebrain are considered important contributors to brain plasticity and neuromodulation. A reduction of cholinergic innervation can lead to pathophysiological ...changes of neurotransmission and is observed in Alzheimer's disease. Here we report on six patients with mild to moderate Alzheimer's disease (AD) treated with bilateral low-frequency deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM). During a four-week double-blind sham-controlled phase and a subsequent 11-month follow-up open label period, clinical outcome was assessed by neuropsychological examination using the Alzheimer's Disease Assessment Scale-cognitive subscale as the primary outcome measure. Electroencephalography and (18)F-fluoro-desoxyglucose positron emission tomography were, besides others, secondary endpoints. On the basis of stable or improved primary outcome parameters twelve months after surgery, four of the six patients were considered responders. No severe or non-transitional side effects related to the stimulation were observed. Taking into account all limitations of a pilot study, we conclude that DBS of the NBM is both technically feasible and well tolerated.
Saving freshwater from salts Cañedo-Argüelles, M.; Hawkins, C. P.; Kefford, B. J. ...
Science (American Association for the Advancement of Science),
02/2016, Letnik:
351, Številka:
6276
Journal Article
Recenzirano
Ion-specific standards are needed to protect biodiversity
Many human activities—like agriculture and resource extraction—are increasing the total concentration of dissolved inorganic salts (i.e., ...salinity) in freshwaters. Increasing salinity can have adverse effects on human health (
1
); increase the costs of water treatment for human consumption; and damage infrastructure e.g., amounting to $700 million per year in the Border Rivers catchment, Australia (
2
). It can also reduce freshwater biodiversity (
3
); alter ecosystem functions (
4
); and affect economic well-being by altering ecosystem goods and services (e.g., fisheries collapse). Yet water-quality legislation and regulations that target salinity typically focus on drinking water and irrigation water, which does not automatically protect biodiversity. For example, specific electrical conductivities (a proxy for salinity) of 2 mS/cm can be acceptable for drinking and irrigation but could extirpate many freshwater insect species (
3
). We argue that salinity standards for specific ions and ion mixtures, not just for total salinity, should be developed and legally enforced to protect freshwater life and ecosystem services. We identify barriers to setting such standards and recommend management guidelines.
Serial X-ray crystallography at free-electron lasers allows to solve biomolecular structures from sub-micron-sized crystals. However, beam time at these facilities is scarce, and involved sample ...delivery techniques are required. On the other hand, rotation electron diffraction (MicroED) has shown great potential as an alternative means for protein nano-crystallography. Here, we present a method for serial electron diffraction of protein nanocrystals combining the benefits of both approaches. In a scanning transmission electron microscope, crystals randomly dispersed on a sample grid are automatically mapped, and a diffraction pattern at fixed orientation is recorded from each at a high acquisition rate. Dose fractionation ensures minimal radiation damage effects. We demonstrate the method by solving the structure of granulovirus occlusion bodies and lysozyme to resolutions of 1.55 Å and 1.80 Å, respectively. Our method promises to provide rapid structure determination for many classes of materials with minimal sample consumption, using readily available instrumentation.
Ten C8C1Im+ (1‐methyl‐3‐octylimidazolium)‐based ionic liquids with anions Cl−, Br−, I−, NO3−, BF4−, TfO−, PF6−, Tf2N−, Pf2N−, and FAP− (TfO=trifluoromethylsulfonate, ...Tf2N=bis(trifluoromethylsulfonyl)imide, Pf2N=bis(pentafluoroethylsulfonyl)imide, FAP=tris(pentafluoroethyl)trifluorophosphate) and two C8C1C1Im+ (1,2‐dimethyl‐3‐octylimidazolium)‐based ionic liquids with anions Br− and Tf2N− were investigated by using X‐ray photoelectron spectroscopy (XPS), NMR spectroscopy and theoretical calculations. While 1H NMR spectroscopy is found to probe very specifically the strongest hydrogen‐bond interaction between the hydrogen attached to the C2 position and the anion, a comparative XPS study provides first direct experimental evidence for cation–anion charge‐transfer phenomena in ionic liquids as a function of the ionic liquid’s anion. These charge‐transfer effects are found to be surprisingly similar for C8C1Im+ and C8C1C1Im+ salts of the same anion, which in combination with theoretical calculations leads to the conclusion that hydrogen bonding and charge transfer occur independently from each other, but are both more pronounced for small and more strongly coordinating anions, and are greatly reduced in the case of large and weakly coordinating anions.
Charges in charged systems: Anion and cation interactions in ionic liquids strongly modify the charges on the ions as proven by XPS, NMR spectroscopy and DFT calculations. The smaller, more basic and, thus, more strongly coordinating the anion, the more pronounced the charge transfer to the cation (see graphic). Hydrogen‐bonding‐type interactions between anion and cation do not significantly influence the amount of charge transferred.
The design of randomised controlled trials (RCTs) should incorporate characteristics (such as concealment of randomised allocation and blinding of participants and personnel) that avoid biases ...resulting from lack of comparability of the intervention and control groups. Empirical evidence suggests that the absence of such characteristics leads to biased intervention effect estimates, but the findings of different studies are not consistent.
To examine the influence of unclear or inadequate random sequence generation and allocation concealment, and unclear or absent double blinding, on intervention effect estimates and between-trial heterogeneity, and whether or not these influences vary with type of clinical area, intervention, comparison and outcome measure.
Data were combined from seven contributing meta-epidemiological studies (collections of meta-analyses in which trial characteristics are assessed and results recorded). The resulting database was used to identify and remove overlapping meta-analyses. Outcomes were coded such that odds ratios < 1 correspond to beneficial intervention effects. Outcome measures were classified as mortality, other objective or subjective. We examined agreement between assessments of trial characteristics in trials assessed in more than one contributing study. We used hierarchical Bayesian bias models to estimate the effect of trial characteristics on average bias quantified as ratios of odds ratios (RORs) with 95% credible intervals (CrIs) comparing trials with and without a characteristic and in increasing between-trial heterogeneity.
The analysis data set contained 1973 trials included in 234 meta-analyses. Median kappa statistics for agreement between assessments of trial characteristics were: sequence generation 0.60, allocation concealment 0.58 and blinding 0.87. Intervention effect estimates were exaggerated by an average 11% in trials with inadequate or unclear (compared with adequate) sequence generation (ROR 0.89, 95% CrI 0.82 to 0.96); between-trial heterogeneity was higher among such trials. Bias associated with inadequate or unclear sequence generation was greatest for subjective outcomes (ROR 0.83, 95% CrI 0.74 to 0.94) and the increase in heterogeneity was greatest for such outcomes standard deviation (SD) 0.20, 95% CrI 0.03 to 0.32. The effect of inadequate or unclear (compared with adequate) allocation concealment was greatest among meta-analyses with a subjectively assessed outcome intervention effect (ROR 0.85, 95% CrI 0.75 to 0.95), and the increase in between-trial heterogeneity was also greatest for such outcomes (SD 0.20, 95% CrI 0.02 to 0.33). Lack of, or unclear, double blinding (compared with double blinding) was associated with an average 13% exaggeration of intervention effects (ROR 0.87, 95% CrI 0.79 to 0.96), and between-trial heterogeneity was increased for such studies (SD 0.14, 95% CrI 0.02 to 0.30). Average bias (ROR 0.78, 95% CrI 0.65 to 0.92) and between-trial heterogeneity (SD 0.37, 95% CrI 0.19 to 0.53) were greatest for meta-analyses assessing subjective outcomes. Among meta-analyses with subjectively assessed outcomes, the effect of lack of blinding appeared greater than the effect of inadequate or unclear sequence generation or allocation concealment.
Bias associated with specific reported study design characteristics leads to exaggeration of beneficial intervention effect estimates and increases in between-trial heterogeneity. For each of the three characteristics assessed, these effects were greatest for subjectively assessed outcomes. Assessments of the risk of bias in RCTs should account for these findings. Further research is needed to understand the effects of attrition bias, as well as the relative importance of blinding of patients, care-givers and outcome assessors, and thus separate the effects of performance and detection bias.
National Institute for Health Research Health Technology Assessment programme.
We experimentally demonstrate a nonlinear detection scheme exploiting time-reversal dynamics that disentangles continuous variable entangled states for feasible readout. Spin-exchange dynamics of ...Bose-Einstein condensates is used as the nonlinear mechanism which not only generates entangled states but can also be time reversed by controlled phase imprinting. For demonstration of a quantum-enhanced measurement we construct an active atom SU(1,1) interferometer, where entangled state preparation and nonlinear readout both consist of parametric amplification. This scheme is capable of exhausting the quantum resource by detecting solely mean atom numbers. Controlled nonlinear transformations widen the spectrum of useful entangled states for applied quantum technologies.
The oceans have absorbed nearly half of the fossil-fuel carbon dioxide (CO2) emitted into the atmosphere since pre-industrial times, causing a measurable reduction in seawater pH and carbonate ...saturation. If CO2 emissions continue to rise at current rates, upper-ocean pH will decrease to levels lower than have existed for tens of millions of years and, critically, at a rate of change 100 times greater than at any time over this period. Recent studies have shown effects of ocean acidification on a variety of marine life forms, in particular calcifying organisms. Consequences at the community to ecosystem level, in contrast, are largely unknown. Here we show that dissolved inorganic carbon consumption of a natural plankton community maintained in mesocosm enclosures at initial CO2 partial pressures of 350, 700 and 1,050 microatm increases with rising CO2. The community consumed up to 39% more dissolved inorganic carbon at increased CO2 partial pressures compared to present levels, whereas nutrient uptake remained the same. The stoichiometry of carbon to nitrogen drawdown increased from 6.0 at low CO2 to 8.0 at high CO2, thus exceeding the Redfield carbon:nitrogen ratio of 6.6 in today's ocean. This excess carbon consumption was associated with higher loss of organic carbon from the upper layer of the stratified mesocosms. If applicable to the natural environment, the observed responses have implications for a variety of marine biological and biogeochemical processes, and underscore the importance of biologically driven feedbacks in the ocean to global change.
We quantify the fraction of the cosmic infrared background (CIB) that originates from galaxies identified in the UV/optical/near-infrared by stacking 81,250 (~35.7 arcmin super(-2)) K-selected ...sources (K sub(AB) < 24.0) split according to their rest-frame U - V versus V - J colors into 72,216 star-forming and 9034 quiescent galaxies, on maps from Spitzer/MIPS (24 mu m), Herschel/PACS (100, 160 mu m), Herschel/SPIRE (250, 350, 500 mu m), and AzTEC (1100 mu m). Of that total, about 95% originates from star-forming galaxies, while the remaining 5% is from apparently quiescent galaxies. The CIB at lambda lap 200 mu m appears to be sourced predominantly from galaxies at z lap 1, while at lambda gap 200 mu the bulk originates from 1 lap z lap 2. Stacking analyses were performed using simstack, a novel algorithm designed to account for possible biases in the stacked flux density due to clustering. It is made available to the public at www.astro.caltech.edu/~viero/viero_homepage/toolbox.html.
The prognosis of metastatic non-small cell lung cancer (NSCLC) is still poor. Activating epithelial growth factor receptor (EGFR) mutations are important genetic alterations with dramatic ...therapeutical implications. Up to now, in contrast to Asian populations only limited data on the prevalence of those mutations are available from patients with Caucasian and especially European ethnicity.
In this multicentre study, 1201 unselected NSCLC patients from Southern Germany were tested in the daily clinical routine for EGFR mutation status.
Activating EGFR mutations were found in 9.8% of all tumours. Mutations in exons 18, 19 and 21 accounted for 4.2%, 61.9% and 33.1% of all mutations, respectively. Non-smokers had a significantly higher rate of EGFR mutations than smokers or ex-smokers (24.4% vs 4.2%; P<0.001). Non-lepidic-non-mucinous adenocarcinomas (G2) accounted for 45.5% of all activating EGFR mutations and 3.5% of all squamous cell carcinomas were tested positive. Thyroid transcription factor 1 protein expression was significantly associated with EGFR mutational status.
These comprehensive data from clinical routine in Germany add to the knowledge of clinical and histopathological factors associated with EGFR mutational status in NSCLC.
Aerosols have important impacts on air quality and climate, but the processes affecting their removal from the atmosphere are not fully understood and are poorly constrained by observations. This ...makes modelled aerosol lifetimes uncertain. In this study, we make use of an observational constraint on aerosol lifetimes provided by radionuclide measurements and investigate the causes of differences within a set of global models. During the Fukushima Dai-Ichi nuclear power plant accident of March 2011, the radioactive isotopes cesium-137 (137Cs) and xenon-133 (133Xe) were released in large quantities. Cesium attached to particles in the ambient air, approximately according to their available aerosol surface area. 137Cs size distribution measurements taken close to the power plant suggested that accumulation-mode (AM) sulfate aerosols were the main carriers of cesium. Hence, 137Cs can be used as a proxy tracer for the AM sulfate aerosol's fate in the atmosphere. In contrast, the noble gas 133Xe behaves almost like a passive transport tracer. Global surface measurements of the two radioactive isotopes taken over several months after the release allow the derivation of a lifetime of the carrier aerosol. We compare this to the lifetimes simulated by 19 different atmospheric transport models initialized with identical emissions of 137Cs that were assigned to an aerosol tracer with each model's default properties of AM sulfate, and 133Xe emissions that were assigned to a passive tracer. We investigate to what extent the modelled sulfate tracer can reproduce the measurements, especially with respect to the observed loss of aerosol mass with time. Modelled 137Cs and 133Xe concentrations sampled at the same location and times as station measurements allow a direct comparison between measured and modelled aerosol lifetime. The e-folding lifetime τe, calculated from station measurement data taken between 2 and 9 weeks after the start of the emissions, is 14.3 days (95 % confidence interval 13.1–15.7 days). The equivalent modelled τe lifetimes have a large spread, varying between 4.8 and 26.7 days with a model median of 9.4 ± 2.3 days, indicating too fast a removal in most models. Because sufficient measurement data were only available from about 2 weeks after the release, the estimated lifetimes apply to aerosols that have undergone long-range transport, i.e. not for freshly emitted aerosol. However, modelled instantaneous lifetimes show that the initial removal in the first 2 weeks was quicker (lifetimes between 1 and 5 days) due to the emissions occurring at low altitudes and co-location of the fresh plume with strong precipitation. Deviations between measured and modelled aerosol lifetimes are largest for the northernmost stations and at later time periods, suggesting that models do not transport enough of the aerosol towards the Arctic. The models underestimate passive tracer (133Xe) concentrations in the Arctic as well but to a smaller extent than for the aerosol (137Cs) tracer. This indicates that in addition to too fast an aerosol removal in the models, errors in simulated atmospheric transport towards the Arctic in most models also contribute to the underestimation of the Arctic aerosol concentrations.
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